The present invention relates to a method of analysing a turbid pharmaceutical sample, e.g. a tablet, a capsulexe2x80x94especially a multiple unit pellet system (MUPS) tablet or capsulexe2x80x94or a similar sample forming a pharmaceutical dose. The invention also relates to an apparatus for performing such a method.
The present invention can optionally be combined with the invention and the spectrometric methods and set-ups as disclosed in applicant""s copending International patent application WO99/49312, filed before the present application but unpublished on the priority date of the present application. Especially, the present invention can be combined with the technique disclosed therein for irradiating two opposite surfaces of an analysed sample, in order to obtain signals representative of the three-dimensional distribution of at least one component in the sample. The content of this International patent application is hereby incorporated by reference.
Non-invasive, non-destructible analysis of whole tablets can be carried out by means of near-infrared (NIR) or Raman spectrometry. Today, NIR spectroscopy is a recognised technique for performing a fast analysis of compounds. The common feature of both these techniques is that they utilise light in the NIR wavelength region (700-2500 nm, specifically 700-1500 nm) where pharmaceutical tablets are relatively transparent (low molar absorptivity). Since light in this region can penetrate compressed powders several millimeters in depth, information on the content can be obtained emanating from the bulk of the tablet and not only from the surface. A practical advantage of using NIR radiation is that diode lasers can be used.
One example of such an analysis is described in U.S. Pat. No. 5,760,399, assigned to Foss NIRsystems Inc. This document discloses an instrument for performing a NIR spectrographic transmission measurement of a pharmaceutical tablet. This instrument is, however, capable of providing only limited information as to the content of a sample, typically the quantity of a particular component in a sample. This prior-art instrument cannot provide detailed information of, for example, the three-dimensional distribution of one or more components in a sample. The technical background on which this limitation is based will be further discussed in connection with the description of the present invention.
The prior art also includes a significant amount of methods for optical imaging of human tissues, in particular for detecting disturbances of homogeneity, such as the presence of a tumour in a human tissue. These methods are generally qualitative measurements, not quantitative, in the sense that they primarily focus on determining the presence and the location of an inhomogeneity. These prior-art methods are not suitable for performing a quantitative analysis on pharmaceutical, turbid samples, such as tablets and capsules, in order to determine e.g. content and structural parameters.
According to a first aspect of the invention, there is provided a method for use in quantitative analysis of a turbid phramaceutical sample, in particular, a pharmaceutical tablet, capsule, bulk powder, or an equivalent pharmaceutical dose.
According to the invention, the method comprises the following steps:
providing an excitation beam of radiation;
irradiating a pharmaceutical, turbid sample with said excitation beam of radiation; and
measuring the intensity of emitted radiation from the thus irradiated sample as a function of both the wavelength of the emitted radiation and the photon propagation time through said sample.
The invention is based on the following principles. A sample to be analysed by a spectrometric transmission and/or reflection measurement presents a number of so called optical properties. These optical properties are (i) the absorption coefficient, (ii) the scattering coefficient and (iii) the scattering anisotropy. Thus, when the photons of the excitation beam propagate through the turbid samplexe2x80x94in transmission and/or reflection modexe2x80x94they are influenced by these optical properties and, as a result, subjected to both absorption and scattering. Photons that by coincidence travel along an essentially straight path through the sample and thus do not experience any appreciable scattering will exit the sample with a relatively short time delay. Photons that are directly reflected on the irradiated surface will also present a relatively short time delay, in the case of measurements on reflected light. On the other hand, highly scattered photons (transmitted and/or reflected) exit with a substantial time delay. This means that all these emitted photonsxe2x80x94presenting different propagation timesxe2x80x94mediate complementary information about the sample.
In a conventional steady state (no time-resolution) measurement, some of that complementary information is added together since the emitted light is captured by a time-integrated detection. Accordingly, the complementary information is lost in a conventional technique. For instance, a decrease in the registered light intensity may be caused by an increase in the sample absorption coefficient, but it may also be caused by a change in the sample scattering coefficient. However, the information about the actual cause is hidden, since all the emitted light has been time-integrated.
According to the invention and in contrast to such prior-art NMR spectroscopy with time-integrated intensity detection, the intensity of the emitted radiation from the sample is measured both as a function of the wavelength and as a function of the photon propagation time through said sample. Thus, the inventive method can be said to be both wavelength-resolved and time-resolved. It is important to note that the method is time-resolved in the sense that it provides information about the kinetics of the radiation interaction with the sample. Thus, in this context, the term xe2x80x9ctime resolvedxe2x80x9d means xe2x80x9cphoton propagation time resolvedxe2x80x9d. In other words, the time resolution used in the invention is in a time scale which corresponds to the photon propagation time in the sample (i.e. the photon transit time from the source to the detector) and which, as a consequence, makes it possible to avoid time-integrating the information relating to different photon propagation times. As an illustrative example, the transit time for the photons may be in the order of 0,1-2 ns. Especially, the term xe2x80x9ctime resolvedxe2x80x9d is not related to a time period necessary for performing a spatial scanning, which is the case in some prior-art NIR-techniques where xe2x80x9ctime resolutionxe2x80x9d is used.
As a result of not time-integrating the radiation (and thereby xe2x80x9chidingxe2x80x9d a lot of information) as done in the prior art, but instead time resolving the information from the excitation of the sample in combination with wavelength resolving the information, the invention makes it possible to establish quantitative analytical parameters of the sample, such as content, concentration, structure, homogeneity, etc.
Both the transmitted radiation and the reflected radiation from the irradiated sample comprise photons with different time delay. Accordingly, the time-resolved and wavelength resolved detection may be performed on transmitted radiation only, reflected radiation only, as well as a combination of transmitted and reflected radiation.
The excitation beam of radiation used in the present invention may include infrared radiation, especially near infrared (NIR) radiation of in the range corresponding to wavelengths of from about 700 to about 1700 nm, particularly from 700 to 1300 nm. However, the excitation beam of radiation may also include visible light (400 to 700 nm) and UV radiation. In this connection, it should also be stated that the term xe2x80x9cexcitationxe2x80x9d should be interpreted as meaning xe2x80x9cilluminationxe2x80x9d, i.e. no chemical excitation of the sample is necessary.
Preferably, the step of measuring the intensity as a function of photon propagation time is performed in time-synchronism with the excitation of the sample. In a first preferred embodiment, this time synchronism is implemented by using a pulsed excitation beam, presenting a pulse train of short excitation pulses, wherein each excitation pulse triggers the intensity measurement. To this end, a pulsed laser system or laser diodes can be used. This technique makes it possible to perform a photon propagation time-resolved measurement of the emitted intensity (transmitted and/or reflected) for each given excitation pulse, during the time period up to the subsequent excitation pulse.
In order to avoid any undesired interference between the intensity measurements relating to two subsequent excitation pulses, such excitation pulses should have a pulse length short enough in relation to the photon propagation time in the sample and, preferably, much shorter than the photon propagation time.
To summaries, in this embodiment of the invention the intensity detection of the emitted radiation associated with a given excitation pulse is time-synchronised with this pulse, and the detection of the emitted light from one pulse is completed before the next pulse.
The data evaluation can be done in different ways. By defining the boundary conditions and the optical geometry of the set-up, iterative methods such as Monte Carlo simulations can be utilised to calculate the optical properties of the sample and indirectly content and structural parameters. Alternatively, a multivariate calibration can be used for a direct extraction of such parameters. In multivariate calibration, measured data is utilised to establish an empirical mathematical relationship to the analytical parameter of interest, such as the content or structure of a pharmaceutical substance. When new measurements are performed, the model can be used to predict the analytical parameters of the unknown sample.
In an alternative embodiment the radiation source is intensity modulated in time. Then, frequency domain spectroscopy can be used for determining phase shift and/or modulation depth of the emitted radiation from the sample. Thus, the phase and/or modulation depth of the emitted sample radiation is compared with those of the excitation radiation. That information can be used to extract information about the time delay of the radiation in the sample. It should be noted that such a frequency domain spectroscopy is also a xe2x80x9ctime-resolvedxe2x80x9d technique according to the invention, since it also provides information about the kinetics of the photon interaction with the sample. With similar mathematical procedures as above, the same quantitative analytical information can be extracted.
A pulsed excitation beam according to the first embodiment, and an intensity modulated excitation beam according to the second embodiment, share the common feature that they make it possible to identifyxe2x80x94in said excitation beamxe2x80x94a specific xe2x80x9cexcitation time pointxe2x80x9d which can be used to trigger the detection of the emitted radiation from the sample, i.e. to time-synchronise the time-resolved detection with the excitation of the sample. This can be performed by letting the pulsed or modulated beam trigger a photodetector or the equivalent, which in its turn triggers the detection unit via suitable time-control circuitry.
The time-resolved detection may be implemented by the use of a time-resolved detector, such as a streak camera. It may also be implemented by the use of a time-gated system, by which the detection of emitted radiation is performed during a limited number of very short time slices instead of the full time course. The time length of each such time slice is only a fraction of the detection time period during which the time resolved detection is performed for each excitation. By measuring several such xe2x80x9ctime slicesxe2x80x9d a coarse time resolution is achieved. An attractive alternative is to measure wavelength resolved spectra at two such time gates, prompt light and delayed light. Furthermore, time-resolved data may be recorded by means of other time-resolved equipment, transient digitizers or equivalent.
The wavelength-resolved detection may be implemented in many different, conventional ways. It may be implemented by the use of one or more single-channel detectors for selecting one or more wavelengths, such as ultrafast photo diodes, photomultipliers, etc, or by the use of a multichannel detector, such as a microchannel plates or a streak camera Use can be made of light dispersive systems, such as (i) a spectrometer, (ii) a wavelength dependent beam splitter, (iii) a non-wavelength dependent beam splitter in combination with a plurality of filters for filtering each of respective components for providing radiation of different wavelength or wavelength band, (iv) a prism array or a lens system separating the emitted radiation from the sample into a plurality of components in combination with a plurality of filters, etc.
In accordance with a further aspect of the invention, there is also provided an apparatus for performing the inventive method, said apparatus having the features as defined in the enclosed claims.
The above and other features and advantages of the invention are defined in the claims and described in greater detail below with reference to the accompanying drawings, which illustrate preferred embodiments.